A Phase I/II Trial of STI571 and High-Dose Cytarabine in Myeloid Blast Crisis of Chronic Myeloid Leukemia
A Phase I/II Trial of STI571 and High-Dose Cytarabine in Myeloid Blast Crisis of Chronic Myeloid Leukemia
Phase I/II trial to study the effectiveness of combining STI571 and chemotherapy in treating patients who have chronic myelogenous leukemia. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. STI571 may stop the growth of leukemia cells. Combining chemotherapy and STI571 may kill more cancer cells
OBJECTIVES:
I. Determine the maximum tolerated dose of high-dose cytarabine when combined with imatinib mesylate in patients with blastic phase chronic myelogenous leukemia.
II. Determine the safety of this regimen in these patients. III. Determine the pharmacokinetics of this regimen in these patients. IV. Determine the frequency of hematologic and cytogenetic responses, duration of response, and survival of patients treated with this regimen.
OUTLINE: This is a multicenter, dose-escalation study of cytarabine.
Phase I: Patients who have not previously received imatinib mesylate receive oral imatinib mesylate daily on days 1-35. Patients who have previously received imatinib mesylate for at least 28 days receive oral imatinib mesylate on days 22-35. All patients receive cytarabine IV over 2 hours every 12 hours on days 29-32. Patients with more than 5% residual blasts in bone marrow on day 28 receive a second course in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of cytarabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that which 2 of 6 patients experience dose-limiting toxicity.
Phase II: Additional patients are treated at the dose level preceding the MTD. Patients are followed monthly.
Inclusion Criteria:
Diagnosis of chronic myelogenous leukemia in myeloid blast crisis
Philadelphia chromosome positive by cytogenetic analysis
bcr/abl translocation by fluorescent in situ hybridization
Ineligible for or refused allogeneic stem cell transplantation
Not previously treated with imatinib mesylate OR currently receiving imatinib mesylate with stable disease on 2 bone marrow biopsies at least 2 weeks apart
Performance status - ECOG 0-2
See Disease Characteristics
Bilirubin less than 3 times upper limit of normal (ULN)
AST and ALT less than 3 times ULN
Creatinine less than 2 times ULN
No New York Heart Association class III or IV heart disease
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective barrier contraception during and for at least 2 weeks after study for female patients and at least 3 months after study for male patients
See Disease Characteristics
No prior allogeneic bone marrow or peripheral blood stem cell transplantation
At least 48 hours since prior interferon alfa
At least 24 hours since prior hydroxyurea
At least 6 weeks since prior busulfan
No other prior chemotherapy for blast crisis (except hydroxyurea)
Concurrent hydroxyurea or anagrelide for severe leukocytosis or thrombocytosis allowed
At least 4 weeks since prior investigational agents